Requirements for successful immunotherapy and chemoimmunotherapy of a murine model of ovarian cancer.

A comprehensive study of nonspecific immunotherapy has been conducted in an established murine model of ovarian cancer in order to determine the relative effectiveness of commonly used bacterial immunostimulants, the importance of the route and schedule of administration of these agents, and their effects in combination with chemotherapy. Implants of 10(5) or 10(6) ovarian tumor cells i.p. kill all syngeneic C3HeB/FeJ mice within 25 days. Corynebacterium parvum (700 microgram/mouse i.p. 24 hr after a 10(5) tumor cell inoculum) cures 75% of the mice; in contrast, neither i.v. nor s.c. administration improves survival rates. After the same tumor challenge, Bacillus Calmette-Guérin was minimally effective at extremely high doses only, while the methanol extraction residue of B. Calmette-Guérin was ineffective. Two days after an implant of 10(6) tumor cells, neither cyclophosphamide, nor cis-diamminedichloroplastinum(II) (cisplatin), nor C. parvum increased survival. Combination of C. parvum with cyclophosphamide or cisplatin resulted in a synergism shown by the 40 and 60% cure rates, respectively. However, combination of C. parvum with an active agent, doxorubicin, resulted in toxicity even in untumored animals. This study demonstrates that therapeutic efficacy of immunotherapy depends critically on the choice of an appropriate agent and route of administration and, to a lesser extent, on the dose and schedule used. The observation provides a rationale for carefully conducted Phase I and Phase II studies of treatment with bacterial immunostimulants, alone or in combination with chemotherapy, in human ovarian cancer.

Lack of histocompatibility antigens on a murine ovarian teratocarcinoma.

We have attempted to generate in vitro lymphocytes cytotoxic to a widely studied model of ovarian cancer in C3HeB/FeJ mice. These attempts were unsuccessful with either syngeneic or allogeneic spleen cells. The following experimental results demonstrated that this murine ovarian tumor lacks histocompatibility antigens. (a) Tumor cells were not lysed by allogeneic lymphocytes presensitized to H-2k spleen cells. (b) Tumor cells did not specifically inhibit the cell-mediated lysis of H-2k spleen cells by presensitized allogeneic lymphocytes. (c) Histoincompatible (H-2b or H-2d) and syngeneic (H-2k) mice all died with identical tumor growth patterns within 25, 30, or 35 days following the i.p. inoculation of 10(6), 10(5), or 10(4) tumor cells, respectively. (d) Tumor cells were not lysed by an anti-H-2k antiserum and complement. (e) Absorption of the anti-H-2k antiserum with tumor cells did not decrease the cytotoxicity of the antiserum. (f) Competitive inhibition of a radioimmunoassay and polyacrylamide gel electrophoresis of immunoprecipitate of radiolabeled tumor extracts failed to demonstrate an H-2 heavy chain, although a normal amount of beta-microglobulin was present. This lack of histocompatibility antigens may explain the failure to generate lymphocytes cytotoxic to this tumor. Thus, this murine ovarian tumor, which has a serologically detectable tumor-associated antigen and can be cured by nonspecific immunotherapy, may provide an excellent model for the study of successful immunotherapy in the absence of histocompatibility antigens and associated cell-mediated reactions.

Objective regressions of T- and B-cell lymphomas in patients following treatment with anti-thymocyte globulin.

We have conducted a clinical trial utilizing anti-thymocyte globulin (ATG) for the treatment of patients with non-Hodgkin's lymphomas. Six patients were treated; 50% reductions in tumor mass of short duration were observed in one patient with a T-cell lymphoma and two patients with B-cell lymphomas. In vitro assays have been performed in an attempt to study the reactivity and potential mechanism of antitumor action of the ATG. The ATG bound to essentially all normal blood mononuclear leukocytes as well as tumor cells from patients with T-, B-, or null cell lymphomas demonstrating its lack of specificity. Furthermore, complement-mediated lysis of normal mononuclear leukocytes, normal T- or B-cells, and tumor cells from two unresponsive patients were all comparable; moreover, since this lysis occurred only at concentrations of ATG that are not attainable in vivo, it is unlikely that complement-mediated cytotoxicity accounts for the responses observed. Peripheral blood lymphocyte counts and total erythrocyte rosettes did decrease during ATG treatment. Thus, objective tumor responses in both B- and T-cell non-Hodgkin's lymphomas can be achieved with a very nonspecific antiserum although significant toxicity resulted. Whether the magnitude or duration of response can be increased with monoclonal antibodies remains to be determined. Future success with serotherapy might require use of either a battery of different monoclonal antibodies or a single monoclonal antibody that can deliver radioisotopes, chemotherapy, or toxins to the tumor cells.

Increased sensitivity of T cells to regulation by normal suppressor cells persists in long-term survivors with Hodgkin's disease.

We have studied the function of T cells in the peripheral blood obtained from long term survivors with Hodgkin's disease in order to determine the sensitivity of those T cells to normal suppressor cell immunoregulatory mechanisms. Concanavalin A-activated suppressor cells from normal donors suppressed the proliferation of lymphocytes obtained from 11 patients (56.8 +/- 3.5 percent) and from 28 allogeneic normal control subjects (39.8 +/- 2.7 percent [p less than 0.001]). When suppressor monocytes from the normal donors were studied, the mean proliferation of lymphocytes from 19 patients was suppressed 76.3 +/- 4.8 percent whereas proliferation of lymphocytes from 26 normal donors was suppressed 46.6 +/- 4.4 percent (p less than 0.0001). There was no tendency for the increased sensitivity to suppression that was observed in either assay system to return to normal as the patients' disease free interval increased from 1.5 years to 12 years. Furthermore, long-term survivors with diffuse histiocytic lymphoma, who had been treated with comparable chemotherapy, had normal sensitivity to the suppressor monocytes (45.1 +/- 3.8 percent). In Hodgkin's disease, the persistent increased sensitivity of T cells to two different normal immunoregulatory cells suggests that the response of the T cell to regulatory signals may be an important cause of the depressed cellular immunity observed in Hodgkin's disease and a clue to the etiology of the disease.

[Indications for radiotherapy and chemotherapy in colorectal cancer]. / Indications des radiothérapie et chimiothérapie dans le cancer colorectal.

The treatment of colorectal cancer is undergoing serious transformation. Surgical techniques have evolved, the role of adjuvant radio- and chemotherapy has been confirmed as an essential part of the current treatment of these cancer and new drugs, established in advanced disease are now being introduced in combination schemes of promise in both palliative and adjuvant chemotherapy.

Characterization of the activity of alpha/beta-triglycidylurazol (TGU; NSC-332488): a new antineoplastic compound.

The antitumour properties of alpha/beta-triglycidylurazol (TGU) were investigated on various transplantable mouse tumour systems. A high rate of cures of P388 and L1210 leukaemias was obtained with this compound. TGU also had an antitumour effect against B16 melanoma, the colon 38 tumour and the advanced RC renal carcinoma, producing a total regression of the tumour. Finally, the marked in vivo activity of TGU against a subline of P388 leukaemia totally resistant to cyclophosphamide (CP), its good water-solubility (7%) and its stability in neutral pH are further elements warranting clinical studies with this agent.

Increased sensitivity to normal adherent suppressor cells in untreated advanced Hodgkin's disease.

Mononuclear leukocytes isolated from the peripheral blood of 10 untreated patients with advanced stages of Hodgkin's disease and 26 normal volunteers were stimulated with allogeneic cells from normal donors in a one-way mixed lymphocyte culture. When the patients' cells were stimulated by an increased number of normal cells, the baseline mixed lymphocyte culture was suppressed 77.1% +/- 4.1%. In contrast, when the normal responder cells were cultured with increased numbers of normal stimulator cells, mean suppression was only 46.6% +/- 4.4% (p less than 0.001), The removal of phagocytic cells from the high concentration of normal stimulators totally abolished the suppression observed with the patients' cells, resulting in a mean increase in stimulation of 84% above that found in the baseline culture. The suppression could also be reversed by depletion of adherent cells from stimulator leukocytes. When adherent and nonadherent stimulator cells were recombined, significant suppression of proliferation was again observed. The increased suppression was not caused by the presence of autologous plasma in patients' cultures, since similar results were obtained utilizing AB serum. The addition of indomethacin to the cultures only partially reversed the suppression observed with the patients' cells. These studies demonstrates that mononuclear leukocytes from the peripheral blood of untreated patients with advanced stages of Hodgkin's disease have increased sensitivity to a normal adherent suppressor cell system.

Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin's disease.

Immunologic studies were done on 47 long-term survivors of Hodgkin's disease who had been treated with MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone). Percentages of E rosettes and mitogen-induced lymphocyte proliferation were significantly reduced compared to those in normal control subjects. There was no tendency for these abnormalities to return to the normal range with increasing disease-free intervals. No abnormalities of B-cell number or function were detected. Long-term survivors of advanced diffuse histiocytic lymphoma treated with comparable chemotherapy, who served as a control population, had significantly higher percentages of E rosettes and no reduction in mitogen-induced lymphocyte proliferation. Thus these persistent immunologic abnormalities cannot be attributed to chemotherapy alone. The presence of similar immunologic abnormalities in untreated patients with Hodgkin's disease of all stages and in patients cured by either MOPP or radiotherapy suggests that depressed cellular immunity may be an inherent characteristic of the person in whom Hodgkin's disease develops.